This proposal is submitted in response to the following Title: Recovery Act Limited Competition: Research to Address the Heterogeneity in Autism Spectrum Disorders (R21). Request for Applications (RFA) Number: RFA-MH-09-172 Abstract: Though most studies have examined immune abnormalities in children with autism, it is also possible that an aberrant immune response in mothers during vulnerable, critical periods of neurodevelopment could produce neuronal injury in the fetal or neonatal brain, and produce long term neurological dysfunction characteristic of autism. We will examine several quantifiable biological signatures of immune cells in blood of mothers of children with autism: (1) RNA levels, (2) functional assays of white blood cells and (3) the presence of antibodies that are directed to fetal-brain proteins. We have preliminary data showing that a number of mothers of children with autism have RNA expression profiles in their peripheral blood that differ from mothers of control children. We have discovered that the function of Natural Killer (NK) cells in blood of a number of children with autism is impaired. We have also discovered that some mothers of children with autism have antibodies in their blood that are directed at fetal-brain proteins. Based upon these promising findings, we propose the following Specific Aims for this exploratory R21. Specific Aim #1. Determine whether there are subgroups of mothers of children with autism with different RNA expression profiles in their peripheral blood that differ from each other and differ from controls. Specific Aim #2: Examine Natural Killer (NK) cell function in mothers of children with autism;whether the NK functional changes are associated with changes of NK gene expression;and whether some of these mothers have autistic children with abnormal NK cell function. Specific Aim #3. Determine whether mothers of children with autism, who have antibodies that are directed at fetal-brain proteins and which are detectable in blood, have abnormal NK function and/or abnormal RNA expression profiles in blood that differ from other mothers of children with autism and differ from mothers of typically developing children. Hypotheses: We postulate that there is a subgroup of mothers with children with autism who has an immune abnormality detectable in peripheral blood that can be assessed using (1) RNA expression in the immune/ white blood cells (2) functional assays of white blood cells and (3) and by showing the presence of antibodies directed to fetal-brain proteins in blood. Significance and Impact. The ability to identify a subgroup of mothers of children with autism into a specific immune-related phenotype will improve the success of linkage and whole genome association studies to detect genes associated with this subgroup. The identification of biological signatures in mothers that are highly associated with having children with autism could eventually lead to the characterization of specific immune abnormalities in the mothers of children with autism and may shed light on the cause(s) of autism in this subgroup and potentially lead to prevention or treatment strategies prior to or during pregnancy. PUBLIC HEALTH RELEVANCE: There has been relatively little attention paid to the immune system of mothers of children with autism. The maternal immune system is important since a dysfunctional immune response during pregnancy might affect the fetal brain and result in autism. Thus, this proposal will focus on the immune system of women with children with autism compared to women of typically developing children.